Cellular mechanisms of axon targeting in the regenerating olfactory system

Chehrehasa, Fatemeh (2007). Cellular mechanisms of axon targeting in the regenerating olfactory system PhD Thesis, School of Biomedical Sciences, University of Queensland.

       
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Author Chehrehasa, Fatemeh
Thesis Title Cellular mechanisms of axon targeting in the regenerating olfactory system
School, Centre or Institute School of Biomedical Sciences
Institution University of Queensland
Publication date 2007
Thesis type PhD Thesis
Supervisor Associate Professor Brian Key
Abstract/Summary Mammalian olfactory neurons reside with the olfactory neuroepithelium lining the nasal cavity and target specific regions of neuropil within the olfactory bulb in the brain referred to as glomeruli. Primary olfactory neurons in the mouse express one of ~1000 odorant receptors. The neurons expressing the same odorant receptor gene are typically restricted in their distribution to one of four broad zones in the olfactory neuroepithelium, and project to at least two topographically-fixed glomeruli, one each on the medial and lateral surfaces of the olfactory bulb. Throughout life, primary olfactory neurons undergo continuous cell turnover. Mature primary olfactory neurons have a limited lifespan and are replaced by proliferating progenitor cells within basal layers of the neuroepithelium. Unlike in other regions of the nervous system this means that new axons are continually growing along the olfactory and navigating to their target sites. A number of candidate guidance molecules have been identified within the olfactory system that contributes in guiding of olfactory axons within olfactory pathway; however the molecular interactions responsible for growth and guidance remain unknown. Furthermore the role of the target tissue, the olfactory bulb, in providing guidance cues to the olfactory axons is unclear. There were three principal aims of the present thesis. First, to investigate the sorting behavior of olfactory and vomeronasal organ axons during regeneration. Second, to understand the underlying role of the olfactory bulb in formation of the outer layers of the olfactory bulb. Third, to assess the role of the olfactory bulb in guiding axons to their glomerular targets during development. The first aim of this thesis was to understand how primary olfactory and vomeronasal organ axons target specific regions of the olfactory bulb. The sorting behaviour of these axons was examined following neonatal unilateral olfactory bulbectomy. Bulbectomy induced widespread ipsilateral death of the primary olfactory and vomeronasal organ neurons within the nasal cavity and vomeronasal organ, respectively. After four weeks, many new sensory axons had re-grown into the cranial cavity and established a prominent plexus with evidence of dense tufts that were similar in gross appearance to glomeruli. Axons expressing the cell adhesion molecule OCAM, which normally innervate the ventrolateral and rostral halves of the main and accessory olfactory bulbs respectively, were found to sort out and segregate from those axons not expressing this molecule within the plexus. Sorting was also observed for axon subpopulations which were expressing specific cell surface glycoconjugates. In addition, vomeronasal organ axons formed large discrete bundles that segregated from main olfactory axons within the plexus. The second aim of the thesis was to understand the underlying role of the olfactory bulb in development of the outer layers of the olfactory bulb. The olfactory bulbs in OMP-IRES-LacZ and P2-IRES-tau-LacZ neonatal mice were unilaterally removed and replaced with artificial biological scaffolds molded into the shape of an olfactory bulb. Regenerating axons projected around the edge of the cranial cavity at the periphery of the artificial scaffold and were able to form an olfactory nerve fibre layer and, to some extent, a glomerular layer. Our results reveal that olfactory axons are able to form rudimentary cytoarchitectonic layers if they are provided with an appropriately shaped biological scaffold. The third aim of this thesis was to understand the role of the olfactory bulb in the formation of the olfactory nerve pathway. A model was developed whereby the gross shape of the olfactory bulb in P2-IRES-tau-LacZ neonatal mice was disrupted without perturbing olfactory nerve connections. It was demonstrated that the topography of axons expressing the P2 odorant receptor was perturbed when the normal shape of the olfactory bulb was altered. P2 axons instead projected to multiple inappropriate glomeruli surrounding their normal target glomerulus. Our results support the hypothesis that local guidance cues in the bulb direct the final targeting of olfactory axons. In conclusion, the results of this thesis revealed that the sorting and convergence of axons occur independently of the olfactory bulb and are probably attributable either to inherent properties of the axons themselves or to interactions between the axons and accompanying glial ensheathing cells. The bulbectomy studies clearly revealed that the olfactory bulb does not provide any tropic substance that either attracts regenerating olfactory axons into the cranial cavity or induces these axons to form a plexus around its outer surface. However, to the shape of the olfactory bulb is important for directing olfactory axons to their appropriate topographic glomerulus. It is postulated that the surface of the olfactory bulb contains topographic guidance cues that direct the final targeting of olfactory axons. The nature of these cues remains to be determined.

 
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Created: Fri, 21 Nov 2008, 15:34:55 EST